Neurotrophic factors are functionally defined as molecules which promote the maintenance and growth of neurons in vitro and in vivo.1 Among such factors are the nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF). Intraventricular administration of NGF to rats and primates reduces cholinergic neuronal degeneration, with potential implications for the treatment of Alzheimer's disease.2a,3 GDNF may have consequences in the treatment of Parkinson's disease.2b However, optimism along these lines is tempered by concerns as to the pharmacokinetics and bioavailability of polypeptidal factors.3 It is in this connection that the discovery of non-peptidal small molecules with neurotrophic properties is potentially of great significance.4 It seems appropriate to explore non-peptidal neurotrophic agents in detail as to their biological function and their usefulness, if any, in the treatment of neurodegenerative diseases. A mastery of the total synthesis of such small-molecule natural products could be most helpful, not only in improving access to these difficultly available agents, but in providing the basis for probing their SAR profiles.
Described below is the total synthesis of the pentacyclic sesquiterpene dilactone, merrilactone A (1). This compound had previously been obtained in 0.004% yield from the methanol extract of the pericarps of Illicium merrillianum.5 Preliminary studies indicated that 1 greatly promotes neurite outgrowth in fetal rat cortical neurons at concentrations as low as 0.1–10 μmol. Further investigations to date have been hampered by the scarcity of the natural merrilactone A.